MEDICAL POLICY I. POLICY POLICY TITLE PLASMA EXCHANGE (PE) POLICY NUMBER MP Original Issue Date (Created): December 1, 2010

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1 Original Issue Date (Created): December 1, 2010 Most Recent Review Date (Revised): January 28, 2014 Effective Date: April 1, 2014 I. POLICY Plasma Exchange (PE) Plasma exchange (PE) may be considered medically necessary for any of the conditions listed below: Autoimmune Severe multiple manifestations of mixed cryoglobulinemia (MC) such as cryoglobulinemic nephropathy, skin ulcers, sensory motor neuropathy, and widespread vasculitis in combination with immunosuppressive treatment; Catastrophic antiphospholipid syndrome (CAPS). Hematologic ABO incompatible hematopoietic progenitor cell transplantation; Hyperviscosity syndromes associated with multiple myeloma or Waldenstrom s macroglobulinemia,; Idiopathic thrombocytopenic purpura (ITP) in emergency situations; Thrombotic thrombocytopenic purpura (TTP); Atypical hemolytic-uremic syndrome; HELLP syndrome of pregnancy (a severe form of preeclampsia, characterized by hemolysis [H], elevated liver enzymes [EL], and low platelet [LP] counts) Myeloma with acute renal failure. Neurological Acute inflammatory demyelinating polyneuropathy (Guillain-Barre syndrome); severity grade 1 2 within 2 weeks of onset; severity grade 3 5 disease, within 4 weeks of onset; and children younger than 10 years old with severe GBS Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP); Page 1

2 Renal Multiple sclerosis; acute fulminant central nervous system (CNS) demyelination; Myasthenia gravis in crisis or as part of preoperative preparation; Paraproteinemia polyneuropathy; IgA, IgG Anti-glomerular basement membrane disease (Goodpasture s syndrome); ANCA-associated vasculitis (e.g., Wegener s granulomatosis) with associated renal failure Dense deposit disease with factor H deficiency and/or elevated C3 Nephritic factor. Transplantation ABO incompatible solid organ transplantation; o Kidney; o Heart (infants); and o Renal transplantation: antibody mediated rejection; HLA desensitization. Focal segmental glomulerulosclerosis after renal transplant. POLICY GUIDELINES Patients receiving plasma exchange (PE) as a treatment of CIDP should meet the diagnostic criteria for chronic inflammatory demyelinating polyneuropathy (CIDP), which are included in an Appendix to this policy. The use of PE in patients with acute, life-threatening complications of chronic autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus (SLE), may need to be considered on an individual basis. An example of such a situation would be the development of a severe vasculitis, in which it is hoped that the use of PE can acutely lower the level of serum autoantibodies until an alternate long-term treatment strategy can be implemented. However, in these situations, the treatment goals and duration of treatment with PE need to be clearly established prior to its initiation; without such treatment goals, the use of an acute short-term course of PE may insidiously evolve to a chronic use of PE with uncertain benefit. Plasma exchange (PE) is considered investigational in all other conditions, including, but not limited, to the following: ABO- incompatible solid organ transplant; liver; Acute disseminated encephalomyelitis; Page 2

3 Acute inflammatory demyelinating polyneuropathy (Guillain-Barre syndrome) in children younger than 10 years old with mild or moderate forms Acute liver failure; Amyotropic lateral sclerosis; ANCA [antineutrophil cytoplasmic antibody]-associated rapidly progressive glomerulonephritis (Wegener s granulomatosis or GPA without renal failure); Aplastic anemia; Asthma; Autoimmune hemolytic anemia; warm autoimmune hemolytic anemia; cold agglutinin disease; Chronic fatigue syndrome; Coagulation factor inhibitors; Cryoglobulinemia; except for severe mixed cryoglobulinemia, as noted above Dermatomyositis and polymyositis; Focal segmental glomerulosclerosis(other than after renal transplant); Heart transplant rejection treatment; Hemolytic uremic syndrome (HUS); typical (diarrheal related); Hyperviscoscity syndromes with renal failure (other than associated with multiple myeloma or Waldenstrom s macroglobulinermia); Idiopathic thrombocytopenic purpura; refractory or non-refractory; Inclusion body myositis; Lambert-Eaton myasthenic syndrome; Multiple sclerosis; chronic progressive or relapsing remitting; Mushroom poisoning; Myasthenia gravis with anti-musk antibodies; Overdose and poisoning (other than mushroom poisoning); Paraneoplastic syndromes; Paraproteinemia polyneuropathy; IgM Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) Pemphigus vulgaris; Phytanic acid storage disease (Refsum s disease); POEMS (polyneuropathy, organomegaly, endocrinopathy, M protein, skin changes); Psoriasis; Red blood cell alloimmunization in pregnancy; Rheumatoid arthritis; Sepsis; Scleroderma (systemic sclerosis); Stiff person syndrome; Page 3

4 Sydenham s chorea (SC); Systemic lupus erythematosus; manifestations other than nephritis; nephritis; and Thyrotoxicosis. There is insufficient evidence to support a conclusion concerning the health outcomes or benefits associated with this procedure for the above listed indications. Cross-reference MP Immune Globulin MP Pheresis and Apheresis Therapy II. PRODUCT VARIATIONS [N] = No product variation, policy applies as stated [Y] = Standard product coverage varies from application of this policy, see below [N] Capital Cares 4 Kids [N] PPO [N] HMO [Y] SeniorBlue HMO* [Y] SeniorBlue PPO* [N] Indemnity [N] SpecialCare [N] POS [Y] FEP PPO** *Refer to Centers for Medicare and Medicaid (CMS) National Coverage Determination (NCD) Apheresis (Therapeutic Pheresis), Apheresis is covered for the following indications: Plasma exchange for acquired myasthenia gravis; Leukapheresis in the treatment of leukemia; Plasmapheresis in the treatment of primary macroglobulinemia (Waldenstrom); Treatment of hyperglobulinemias, including (but not limited to) multiple myelomas, cryoglobulinemia and hyperviscosity syndromes; Plasmapheresis or plasma exchange as a last resort treatment of thromobotic thrombocytopenic purpura (TTP); Plasmapheresis or plasma exchange in the last resort treatment of life threatening rheumatoid vasculitis; Plasma perfusion of charcoal filters for treatment of pruritis of cholestatic liver disease; Plasma exchange in the treatment of Goodpasture's Syndrome; Page 4

5 Plasma exchange in the treatment of glomerulonephritis associated with antiglomerular basement membrane antibodies and advancing renal failure or pulmonary hemorrhage; Treatment of chronic relapsing polyneuropathy for patients with severe or life threatening symptoms who have failed to respond to conventional therapy; Treatment of life threatening scleroderma and polymyositis when the patient is unresponsive to conventional therapy; Treatment of Guillain-Barre Syndrome; and Treatment of last resort for life threatening systemic lupus erythematosus (SLE) when conventional therapy has failed to prevent clinical deterioration. ** The FEP program dictates that all drugs, devices or biological products approved by the U.S. Food and Drug Administration (FDA) may not be considered investigational. Therefore, FDAapproved drugs, devices or biological products may be assessed on the basis of medical necessity. III. DESCRIPTION/BACKGROUND Plasma exchange (PE) is a procedure in which the plasma is isolated, then discarded and replaced with a substitution fluid such as albumin. Plasma exchange is a nonspecific therapy, since the entire plasma is discarded. PE has been used in a wide variety of conditions including the treatment of neurological disease (e.g., Guillain-Barre) and hematological disorders (e.g., thrombotic thrombocytopenic purpura [TTP]). The terms therapeutic apheresis, plasmapheresis, and plasma exchange (PE) are often used interchangeably, but when properly used denote different procedures. The American Society for Apheresis (ASFA) definitions for these procedures are as follows: Apheresis: A procedure in which blood of the patient or donor is passed through a medical device which separates out one or more components of blood and returns remainder with or without extracorporeal treatment or replacement of the separated component. Plasmapheresis: A procedure in which blood of a patient or the donor is passed through a medical device which separates out plasma from the other components of blood and the plasma is removed (i.e., less than 15% of total plasma volume) without the use of replacement solution. Plasma exchange: A therapeutic procedure in which blood of the patient is passed through a medical device which separates out plasma from other components of blood, the plasma is removed and replaced with a replacement solution such as colloid solution (e.g., albumin and/ or plasma) or combination of crystalloid/colloid solution. This policy addresses only plasma exchange as a therapeutic apheresis procedure. The rationale for PE is based on the fact that circulating substances, such as toxins or autoantibodies, can accumulate in the plasma. Also, it is hypothesized that removal of Page 5

6 these factors can be therapeutic in certain situations. PE is essentially a symptomatic therapy, since it does not remove the source of the pathogenic factors. Therefore the success of PE will depend on whether the pathogenic substances are accessible through the circulation, and whether their rate of production and transfer to the plasma component can be adequately addressed by PE. For example, PE can rapidly reduce levels of serum autoantibodies; however, through a feedback mechanism, this rapid reduction may lead to a rebound overproduction of the same antibodies. This rebound production of antibodies is thought to render the replicating pathogenic clone of lymphocytes more vulnerable to cytotoxic drugs; therefore, PE is sometimes used in conjunction with cyclophosphamide. Applications of PE can be broadly subdivided into two general categories: 1) acute selflimited diseases, in which PE is used to acutely lower the circulating pathogenic substance; and 2) chronic diseases, in which there is ongoing production of pathogenic autoantibodies. Because PE does not address underlying pathology, and, due to the phenomenon of rebound antibody production, its use in chronic diseases has been more controversial than in acute self-limited diseases. Conditions associated with hyperviscosity Serum hyperviscosity is most commonly related to overproduction of immunoglobulins and thus is seen in association with B-cell lymphocyte neoplasms such as multiple myeloma and Waldenstrom s macroglobulinemia. Symptoms of hyperviscosity include bleeding disorders, retinopathy, and neurologic disorders including stroke. Treatment is principally directed at the underlying disorder, but PE may be used to acutely lower the serum viscosity. Acute exacerbations of myasthenia gravis Myasthenia gravis is an autoimmune disease with autoantibodies directed against the postsynaptic membrane of the muscle end-plate. Clinically, the disease is characterized by fatigable weakness of voluntary muscles. Initial treatment focuses on the use of cholinesterase inhibitors to overcome the postsynaptic blockade. Immunosuppressant drugs including corticosteroids and azathioprine are also effective. PE has been used as a short-term therapy in patients with acute exacerbations associated with severe weakness. Guillian-Barré syndrome Guillain-Barré syndrome is an acute demyelinating neuropathy whose severity is graded on a scale of 1 5. The beneficial effect of plasma exchange has been observed regardless of severity of illness. PE is often used for those patients with grades 3 5 disease who do not initially respond to prednisone. Page 6

7 Rapidly progressive glomerulonephritis (RPGN) including Goodpasture s syndrome RPGN is a general term describing the rapid loss of renal function in conjunction with the finding of glomerular crescents on renal biopsy specimens. There are multiple etiologies of RPGN including vasculitis, the deposition of anti-glomerular basement membrane (GBM) antibodies as seen in Goodpasture s syndrome, or the deposition of immune complexes as seen in various infectious diseases or connective tissue diseases. RPGN may also be idiopathic. Because many cases of RPGN represent an immune-mediated disease of acute onset, RPGN was an early focus of PE research. Thrombotic thrombocytopenic purpura (TTP) Hemolytic uremic syndrome (HUS) Once considered distinct syndromes, TTP and HUS are now considered different manifestations of the same disease process, i.e., thrombotic microangiopathy. The classic signs and symptoms include fever, thrombocytopenia, microangiopathic hemolytic anemia, neurologic abnormalities, and renal involvement. TTP-HUS may be seen in association with other conditions, such as pregnancy or HIV infection. PE has become the primary treatment for TTP-HUS, although a rationale for its effectiveness is unknown. PE is performed daily until a response is noted; the length of treatment averages about once a month, with increasing intervals between PE treatments. Idiopathic thrombocytopenic purpura (ITP) ITP is an acquired disease of either adults or children characterized by the development of autoantibodies to platelets. Management of acute bleeding due to thrombocytopenia typically involves immediate platelet transfusion, occasionally in conjunction with a single infusion of intravenous immunoglobulin (IVIg). PE has been occasionally used in emergency situations. PE does not appear to have a role in chronic ITP. HELLP syndrome of pregnancy The HELLP syndrome of pregnancy is a severe form of preeclampsia, characterized by hemolysis (H), elevated liver enzymes (EL), and low platelet (LP) counts. The principal form of treatment is delivery of the fetus. However, for patients with severe thrombocytopenia, PE may be indicated if the fetus cannot safely be delivered, or if the maternal thrombocytopenia persists into the postnatal period. Post-transfusion purpura Post-transfusion purpura is a rare disorder characterized by an acute severe thrombocytopenia occurring about 1 week after a blood transfusion in association with a high titer of anti-platelet alloantibodies. Due to its rapid effect, PE is considered the initial treatment of choice. Page 7

8 Acute fulminant CNS demyelination Multiple sclerosis and other idiopathic inflammatory demyelinating diseases may present with an acute fulminant onset, which may proceed to severe cognitive dysfunction, hemiplegia, paraplegia, or quadriplegia. Chronic inflammatory demyelinating polyneuropathy (CIDP) CIDP is a symmetric polyneuropathy associated with both motor and sensory deficits. The disease course may present as either a relapsing/fluctuating or slowly progressive disease. PE is reserved for those patients who do not respond to treatment with prednisone. PE may be required on a chronic basis, its frequency titrated according to the durability of the patient s response. Some of the symptoms of CIDP may overlap with those of chronic fatigue syndrome. However, the American Academy of Neurology has established diagnostic guidelines for CIDP, which are summarized in an Appendix to this policy. Paraproteinemic polyneuropathy A monoclonal immunoglobulin (paraprotein) is found in the serum or urine of approximately 10% of patients with idiopathic polyneuropathy, typically occurring in the context of a monoclonal gammopathy of undetermined significance (MGUS). In addition, approximately 25% of patients with CIDP may have a monoclonal gammopathy. The gammopathy is typically an IgM (in which it is often directed against myelin-associated proteins or the ganglioside GM-1) or less commonly IgG or IgA. Multiple sclerosis Multiple sclerosis (MS) is an inflammatory demyelinating disease, the etiology of which has remained frustratingly elusive; both environmental and genetic factors are thought to play a role. Laboratory abnormalities suggest that MS is an immune-mediated disease. PE has been used primarily as a technique to either shorten the duration of an acute attack or to reduce the number of acute attacks. Paraneoplastic neuromuscular syndromes Paraneoplastic neuromuscular syndromes are characterized by the production of tumor antibodies that cross-react with the patient s nervous system tissues. In many cases, the paraneoplastic syndrome may be the initial manifestation of the tumor, and in other instances the symptoms of the syndrome are more disabling than the tumor itself. The Lambert-Eaton myasthenic syndrome (LEMS), characterized by proximal muscle weakness of the lower extremities and associated most frequently with small cell lung cancer, is the most common paraneoplastic syndrome. Although presence of LEMS should prompt a search for a lung primary tumor, the syndrome may also occur idiopathically. Other syndromes include paraneoplastic sensory neuropathy, encephalomyelitis, cerebellar degeneration, or opsoclonus/myoclonus (related to the Page 8

9 presence of anti-hu antibody, or in the case of cerebellar degeneration, anti-purkinje cell antibodies). Paraproteinemic immunoglobulin M can also be associated with a demyelinating polyneuropathy. Although treatment of the underlying primary tumor is the cornerstone of treatment, PE has also been investigated due to the presence of circulating autoantibodies. Stiff Man syndrome Stiff man syndrome is an autoimmune disorder characterized by involuntary stiffness of axial muscles and intermittent painful muscle spasm. Symptoms are related to the autoantibodies directed against glutamic acid decarboxylase in the nervous system. Stiff man syndrome may be idiopathic in nature, or seen in association with thymoma, Hodgkin's disease, and small cell lung, colon, or breast cancer. Pemphigus Pemphigus is an autoimmune blistering skin disease that is characterized by serum antibodies that bind to squamous epithelia. Clinically, it is characterized by flaccid bullae that rupture and leave areas of denuded skin, creating serious problems of secondary infection and fluid balance. Steroids or other immunosuppressants are the most common forms of treatment, but the high doses of steroids can produce significant side effects. PE has been investigated in patients refractory or intolerant to steroids or other immunosuppressant therapies. Autoimmune connective tissue diseases This family of diseases includes systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), systemic sclerosis (also referred to as scleroderma), polymyositis, and dermatomyositis. Inclusion body myositis is the most commonly acquired inflammatory myopathy in patients older than age 50 years, characterized by weakness of the quadriceps, biceps, and triceps. When PE first became available during the 1970s and early 1980s, there was considerable interest and enthusiasm for the use of PP/PE for these autoimmune diseases. However since that time, successive randomized controlled trials (RCTs) have not validated the role of PE as a treatment of the chronic phase of these conditions. Cryoglobulinemia There are several types of cryoglobulinemia. Type I is associated with hematological disorders. Types II and III are considered mixed cryoglobulins (MC). MC syndrome is a consequence of immune-complex mediated vasculitis and may be associated with infectious and systemic disorders (e.g., hepatitis C virus). Plasmapheresis in the setting of solid organ transplantation Page 9

10 Acute rejection after transplant can be broadly divided into two categories, the more common acute cellular rejection (ACR) related to activation of T cells, and the less common antibody-mediated rejection reaction (AMR) related to the presence of antidonor antibodies. While ACR typically responds to immunologic therapy directed at T cells, AMR does not, and, as such, has also been referred to as steroid resistant rejection. The risk of AMR is related to the presence of preformed allo-antibodies in the recipient due to prior blood transfusions, transplants, or pregnancies. The presence of allo-antibodies is assessed by using a panel reactive antibody (PRA) screen, which combines the recipient s serum with samples of antigen containing cells taken from 60 individuals representative of the potential donor pool. The percentage PRA is the percentage of positive reactions. Those with a PRA >20% are referred to as sensitized, and these patients often have prolonged waiting times to identify a compatible donor. Living donor kidney transplants have also been performed using ABO mismatched donor organs. These recipients are also at risk of AMR. Plasmapheresis has been used as a technique to desensitize high-risk patients prior to transplant, and also as a treatment of AMR occurring after transplant. Prior to transplant, plasmapheresis has been most commonly used to desensitized patients receiving an ABO mismatched kidney, often in combination with a splenectomy. As a treatment of AMR, plasmapheresis is often used in combination with intravenous immunoglobulin (IVIg) or anti-cd20 therapy (i.e., Rituxan). Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections (PANDAS) and Sydenham s chorea (SC) PANDAS is defined as rapid, episodic onset of obsessive-compulsive disorder (OCD) and/or tic disorder symptoms after a group A Β-hemolytic streptococcal infection (GABHS). The current hypothesis for the pathology of PANDAS is that a streptococcal infection occurring in a vulnerable host causes antibody production and these antibodies cross-react with the cellular components of the basal ganglia. SC is the neurological manifestation of acute rheumatic fever. The choreatic symptoms of Sydenham s chorea are characterized by involuntary rapid and jerky movements that affect the extremities, trunk, and face. SC is generally a self-limited disorder with symptoms resolving in weeks to months. At present, there has been no clearly effective immunomodulatory treatment (i.e., IVIg, plasma exchange), for PANDAS or SC. IV. RATIONALE Autoimmune Diseases One potential type of evidence in support of the clinical effectiveness of plasma exchange (PE) in treating autoimmune diseases is the identification of a pathogenic component of plasma that Page 10

11 is reliably eliminated by plasmapheresis. (1) Although many laboratory abnormalities are associated with autoimmune connective tissue diseases, it is unclear which, if any, cause the clinical manifestations of the disease. Furthermore, it is not known to what extent plasma levels parallel clinical disease. For example, in many of the controlled trials discussed as follows, PE reliably reduced circulating autoantibodies and immune complexes, but without demonstrable clinical benefit. It may be that the patient had already suffered irreversible damage or that the pathogenesis of the disease was a local process unrelated to circulating factors. Over the past 10 years, randomized trials of PE have been conducted and, in general, have shown a lack of effectiveness as treatment of chronic autoimmune diseases. Clinical results of randomized trials of plasmapheresis for specific chronic autoimmune diseases are discussed here. Systemic Lupus Erythematosus Reporting on the results of a randomized controlled trial (RCT), Lewis and colleagues concluded that PE had no benefit in patients with systemic lupus and glomerulonephritis compared to a standard therapy regimen of prednisone and cyclophosphamide. (2) Plasmapheresis has also been investigated as a technique to improve the effectiveness of cyclophosphamide therapy. For example, it is thought that the acute lowering of pathogenic autoantibodies with plasmapheresis may result in their rebound production. It is hoped that the pathogenic lymphocytes would be more sensitive to cyclophosphamide at this point. Danieli and colleagues reported on a prospective nonrandomized trial of 28 patients with proliferative lupus nephritis; 12 underwent synchronized plasmapheresis and pulse cyclophosphamide therapy, while the remaining 16 underwent cyclophosphamide alone. (3) While plasmapheresis was associated with a decreased time to remission of renal disease, at the end of the 4-year follow-up, there was no difference in outcome. Multiple Sclerosis (MS) There have been several RCTs of PE in patients with MS that have reported inconclusive results. Khatri and colleagues studied 54 patients with chronic progressive MS randomized to receive sham or true PE. (4) The degree of improvement in the PE group was greater than that in the control group. Weiner et al. reported on a study that randomized patients with acute attacks of MS to receive either PE or sham treatments; there was no statistical difference in improvement between groups, although patients receiving PE did have a faster recovery rate from acute attacks. (5) A Canadian trial randomized 168 patients with progressive MS to receive either PE or immunosuppressive therapy. (6) There were no significant differences in the rates of treatment failures between groups. Lambert-Eaton Myasthenic Syndrome (LEMS) and Other Paraneoplastic Syndromes Paraneoplastic neuromuscular syndromes are characterized by the production of tumor antibodies that cross-react with the patient s nervous system tissues. The Lambert-Eaton myasthenic syndrome (LEMS), characterized by proximal muscle weakness of the lower Page 11

12 extremities and associated most frequently with small cell lung cancer, is the most common paraneoplastic syndrome. The presumed autoimmune nature of LEMS and other paraneoplastic syndromes led to the use of a variety of immunomodulatory therapies, including PE. However, there are minimal data in the published literature and no controlled trials. The largest case series focusing on LEMS was reported by Tim and colleagues and included 73 patients with LEMS, 31 of whom were found to have lung cancer. (7) Although detailed treatment strategies are not provided, 19 underwent plasmapheresis, with 27% reporting a moderate to marked response. However, the improvement after plasmapheresis, even when marked was only transient. Patients also received other therapies, for example, various chemotherapy regimens for the underlying lung cancer. In addition, 53 of the 73 patients received 3,4 diaminopyridine, with 79% reporting marked or moderate responses. A small RCT of 3,4 diaminopyridine has also reported positive results, confirming other anecdotal reports. (8) Anderson and colleagues reported on a case series of 12 patients with paraneoplastic cerebellar degeneration. Although plasmapheresis was associated with an acute drop in the autoantibody titer, only 2 patients showed a minor improvement in neurologic symptoms. (9) Rheumatoid Arthritis In 1983, Dwosh and colleagues reported on 26 patients with chronic rheumatoid arthritis randomized in a crossover design to either true or sham PE. The authors concluded that PE did not have any clinical benefit despite impressive laboratory changes. (10) Polymyositis/Dermatomyositis Miller and colleagues conducted a randomized trial of PE in the treatment of 39 patients with polymyositis and dermatomyositis and found that it was no more effective than sham pheresis. (11) Pemphigus Pemphigus is an autoimmune blistering skin disease that is characterized by serum antibodies that bind to squamous epithelia. Steroids or other immunosuppressants are the most common forms of treatment, but the high doses of steroids can produce significant side effects. Guillaume and colleagues reported on a study of 40 patients with pemphigus randomized to receive either prednisone alone or prednisone plus plasmapheresis. (12) The goal of the study was to determine whether plasmapheresis could reduce the required dose of steroids, thus limiting its toxicity. Unfortunately, disease control in the two groups was the same, and the authors concluded that plasmapheresis in conjunction with low-dose steroids is not effective in treating pemphigus. Stiff Man (aka Stiff Person) Syndrome Stiff man syndrome is an autoimmune disorder characterized by involuntary stiffness of axial muscles and intermittent painful muscle spasm. Stiff man syndrome may be idiopathic in Page 12

13 nature or seen in association with thymoma, Hodgkin's disease, and small cell lung; colon; or breast cancer. The mainstay of treatment of stiff man syndrome is diazepam. The published literature regarding plasmapheresis consists of small case series and anecdotal reports. (13-15) Cryoglobulinemia There are several types of cryoglobulinemia. Type I is associated with hematologic disorders. Types II and III are considered mixed cryoglobulins. Mixed cryoglobulin syndrome is a consequence of immune-complex mediated vasculitis and may be associated with infectious and systemic disorders (e.g., hepatitis C virus). In 2010, Rockx and Clark published a review of studies evaluating PE for treating cryoglobulinemia that included at least 5 patients. (16) They identified 11 studies with a total of 156 patients. The authors concluded, The quality and variability of the evidence precludes a meta-analysis or even a systematic analysis. However, these studies weakly support the use of plasma exchange largely on a mechanistic basis. Hematologic Thrombotic Thrombocytopenic Purpura (TTP) and Haemolytic Uraemic Syndrome (HUS) Once considered distinct syndromes, TTP and HUS are now considered different manifestations of the same disease process, i.e., thrombotic microangiopathy. In 2009, a systematic review evaluated the benefits and harms of different interventions for HUS and TTP (separately). (17) Interventions compared with placebo or supportive therapy or a comparison of two or more interventions. Interventions examined included heparin, aspirin/dipyridamole, prostanoids, ticlopidine, vincristine, fresh frozen plasma (FFP) infusion, plasmapheresis with fresh frozen plasma, systemic corticosteroids, Shiga toxin-binding agents, or immunosuppressive agents. For TTP, 6 RCTs (n=331 participants) were identified evaluating PE with FFP as the control. Interventions tested included antiplatelet therapy plus PE with FFP, FFP transfusion, and PE with cryosupernatant plasma. Two studies compared plasma infusion (PI) to PE with FFP and showed a significant increase in failure of remission at 2 weeks (risk ratio [RR]: 1.48) and all-cause mortality (RR: 1.91) in the PI group. The authors concluded that PE with fresh frozen plasma is the most effective treatment available for TTP. Seven RCTs included children with HUS. None of the assessed interventions was superior to supportive therapy alone for all-cause mortality, neurological/extrarenal events, renal biopsy changes, proteinuria, or hypertension at the last follow-up visit. Bleeding was significantly higher in those receiving anticoagulation therapy compared to supportive therapy alone (RR: 25.89). For patients with HUS, supportive therapy including dialysis was the most effective treatment. All studies in HUS have been conducted in the diarrheal form of the disease. There were no RCTs evaluating the effectiveness of any interventions on patients with atypical HUS who have a more chronic and relapsing course. A recent review article by Noris and Remuzzi describes the data supporting use of PE in the atypical form of this disease, with results showing remission in up to 60% of patients. (18) Page 13

14 Because the available evidence for patients with typical HUS shows supportive therapy, including dialysis, to be the most effective treatment, all studies in HUS have been conducted with patients with the diarrheal (typical) form of the disease; the use of PE for the treatment of typical HUS is inadequate to draw clinical conclusions. PE for HUS was considered medically necessary in previous updates. PE remains medically necessary for atypical HUS. Idiopathic Thrombocytopenic Purpura (ITP) ITP is an acquired disease of either adults or children characterized by the development of autoantibodies to platelets. Management of acute bleeding due to thrombocytopenia typically involves immediate platelet transfusion, occasionally in conjunction with a single infusion of intravenous immunoglobulin (IVIg). PE has been occasionally used in emergency situations. Post-transfusion Purpura Post-transfusion purpura is a rare disorder characterized by an acute severe thrombocytopenia occurring about 1 week after a blood transfusion in association with a high titer of anti-platelet alloantibodies. Due to its rapid effect, PE is considered the initial treatment of choice. HELLP Syndrome of Pregnancy The HELLP syndrome of pregnancy (characterized by hemolysis [H], elevated liver enzymes [EL], and low platelet [LP] counts) is a severe form of preeclampsia, characterized by hemolysis, elevated liver enzymes, and low platelet counts. The principal form of treatment is delivery of the fetus. However, for patients with severe thrombocytopenia, PE may be indicated if the fetus cannot safely be delivered, or if the maternal thrombocytopenia persists into the postnatal period. Neurological Guillain-Barré Syndrome (GBS) Guillain-Barré syndrome is an acute demyelinating neuropathy whose severity is graded on a scale of 1 5 (the disability scale is summarized in the Appendix to this policy). In 2012, The Cochrane Collaboration published an updated systematic review of the evidence concerning the efficacy of PE for treating GBS. (19) Six eligible trials (n=649) were identified comparing PE versus supportive treatment alone. No additional trials were published since the 2002 review. The primary outcome measures of the review included time to recover walking with aid and time to onset of motor recovery in mildly affected patients. A pooled analysis of data from 3 trials found that PE significantly increased the proportion of patients who recovered the ability to walk with assistance after 4 weeks (RR: 1.60, 95% confidence interval [CI]: 1.19 to 2.15). Data on time to onset of motor recovery were not pooled. Pooled analyses found that PE led to significant improvement in secondary outcomes including reduced time to recover walking without aid, increased likelihood of full muscle strength recovery and reduced likelihood of severe motor sequelae. However, there was a significantly higher risk of relapse Page 14

15 in the group that received PE compared to supportive treatment alone (RR: 2.89, 95% CI: 1.05 to 7.93, 6 trials). A 2007 systematic review evaluated the available randomized trials of immunotherapy to treat GBS. (20) In 4 trials with severely affected adult participants (n=585), those treated with plasma exchange (PE) improved significantly more on the disability scale 4 weeks after randomization than those who were not (weighted mean difference [WMD]: -0.89; range: 1.14 to -0.63). In 5 trials (n=582), the improvement on the disability grade scale with IVIg was very similar to that with PE, WMD: (range: to 0.20). There was also no significant difference between IVIg and PE for any of the other outcome measures. There was 1 trial that included patients (n=91) with the mild form of GBS who were able to walk unaided at enrollment. Patients were randomized to receive either 2 sessions of PE in 3 days or supportive care. The number of patients with one or more grades of improvement at 1 month was significantly greater, 26/45 in the treated compared to the control group, 13/45. Fewer patients in the PE-treated group had clinical deterioration (4%) as compared to the control group (39%) or required ventilation; PE group (2% ) versus the control group (13%). In 1 trial (n=148), following PE with IVIg, did not produce significant extra benefit. Limited evidence from 3 open trials in children suggested that IVIg hastens recovery compared with supportive care alone. None of the treatments significantly reduced mortality. The authors concluded that since approximately 20% of patients die or have persistent disability despite immunotherapy, more research is needed to identify better treatment regimens and new therapeutic strategies. In 2003, a report of the Quality Standards Subcommittee of the American Academy of Neurology (AAN), Practice parameter: immunotherapy for Guillain-Barré syndrome, was published. (21) The following are the key findings: 1) treatment with PE or IVIg hastens recovery from Guillain-Barré syndrome; 2) combining the 2 treatments is not beneficial; and 3) steroid treatment given alone is not beneficial. The AAN s recommendations are: 1) PE is recommended for nonambulant adult patients with GBS who seek treatment within 4 weeks of the onset of neuropathic symptoms (PE should also be considered for ambulant patients examined within 2 weeks of the onset of neuropathic symptoms); 2) IVIg is recommended for nonambulant adult patients with GBS within 2 or possibly 4 weeks of the onset of neuropathic symptoms (the effects of PE and IVIg are equivalent); 3) corticosteroids are not recommended for the management of GBS; 4) sequential treatment with PE followed by IVIg, or immunoabsorption followed by IVIg is not recommended for patients with GBS; and 5) PE and IVIg are treatment options for children with severe GBS. A 2011 RCT from Iran addresses PE for treating young children with severe GBS. (22) The study included 41 children with GBS who required mechanical ventilation and had muscle weakness for no more than 14 days. Patients were randomized to receive PE (n=21) or intravenous immunoglobulin (IVIg) (n=20). Mean age of the patients was 96 months in the PE group and 106 months in the IVIg group. Duration of ventilation, the primary outcome, was a mean of 11 days (standard deviation [SD]=1.5) in the PE group and 13 days (SD=2.1) in the Page 15

16 IVIg group, p= Duration of stay in the intensive care unit, a secondary outcome, was 15.0 days (SD=2.6 days) in the PE group and 16.5 days (SD=2.1 days) in the IVIg group; p=0.94. In conclusion, the available evidence is sufficient regarding PE for the treatment of patients with all severity grades of GBS. This therapy has a beneficial impact on net health outcome for all severity grades. The published studies are insufficient regarding PE for treatment of GBS in the pediatric population. However, based on limited published data, as well as extrapolated data from studies in adults and clinical input, PE may be considered as a treatment option for children younger than 10 years-old with severe GBS. Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP) A 2012 Cochrane review by Mehnidiratta and Hughes identified 2 randomized trials on PE for CIDP. (23) Both trials were considered to be of high quality, but both had small sample sizes. One trial with 29 patients used a parallel design and compared PE to sham treatment. The other study included 15 patients and used a cross-over design to compare PE and sham treatment. A pooled analysis of data from the 2 trials found a statistically significantly greater improvement in impairment after 4 weeks with PE versus sham (mean difference 31 points on the Neuropathy Impairment Score, 95% CI: 16 to 45 points). The scale ranges from 0 (normal) to 280 (maximally affected). Data on other outcomes were not suitable for pooled analysis. Acute Fulminant Central Nervous System (CNS) Demyelination The policy statement, which suggests that plasmapheresis may be considered medically necessary in patients with acute fulminant CNS demyelination, is based on the results of a randomized, double-blinded trial, in which 22 patients with MS or other acute idiopathic inflammatory demyelinating diseases of the CNS were enrolled a minimum of 14 days after having failed to respond to at least 5 days of high-dose corticosteroids. (24) Patients were randomized to receive either 7 real or sham PE procedures over a 14-day period. The primary outcome was a targeted neurologic deficit (i.e., aphasia, cognitive dysfunction, etc.). Overall, moderate to marked improvement of the targeted outcome was obtained in 42% of the treatment group, compared to only 6% in the placebo group. Paraproteinemic Polyneuropathies A randomized, double-blinded trial compared PE to sham treatment in 39 patients with monoclonal gammopathy of undetermined significance (MGUS)-associated polyneuropathy. (25) After twice weekly PE for 3 weeks, the treatment group reported improvements in neurologic function in the IgG and IgA groups but not the IgM MGUS groups. In addition, those from the sham group who were later crossed over to the PE group also reported improvement. Page 16

17 Myasthenia Gravis A randomized trial from China was published in (26) Liu and colleagues assigned 40 patients with late-onset myasthenia gravis to treatment with double-filtration plasmapheresis (n=15), immunoadsorption (IA) (n=10), or intravenous immune globulin (n=15). Treatment was clinically effective, defined as at least a 50% improvement in the relative symptom score, in 12 of 15 (80%) of the plasmapheresis group, 7 of 10 (70%) in the immunoadsorption group, and 6 of 15 (40%) of the immune globulin group. The clinical efficacy rate was significantly higher in both the plasmapheresis and immunoadsorption groups compared to the immune globulin group (p<0.05). Findings were similar for other outcomes; the study was limited by the small sample size. A 2011 RCT from Germany randomized patients with myasthenic crisis to treatment with PE (n=10) or immunoadsorption (IA) (n=9). (27) In both groups, 3 apheresis treatments were performed within 7 days; patients could have additional treatments if needed. A total of 16/19 (84%) of patients, 8 in each group, completed the study and were included in the efficacy analysis. The mean number of treatments was 3.5 in the PE group and 3.4 in the IA group (p>0.05). The primary outcome was change in the modified clinical score (maximum of 3 points) on day 14 after the last treatment. The baseline modified clinical score was 2.6 in the PE group and 2.5 in the IA group. At day 14, score improvement was 1.6 points in the PE group and 1.4 points in the IA group; p>0.05. Within the 180 days after treatment, 1 patient in the PE group and 3 patients in the IA group experienced another myasthenic crisis; the number of events was too small for meaningful statistical analysis for this outcome. There were no statistically significant differences in outcomes in this study, but the sample was very small and the study was probably underpowered. Renal Rapidly Progressive Glomerulonephritis (RPGN) RPGN is a general term describing the rapid loss of renal function in conjunction with the finding of glomerular crescents on renal biopsy specimens. There are multiple etiologies of RPGN including vasculitis, the deposition of anti-glomerular basement membrane (GBM) antibodies as seen in Goodpasture s syndrome, or the deposition of immune complexes as seen in various infectious diseases or connective tissue diseases. PE has long been considered a treatment alternative in immune-mediated RPGN. However, there have been few controlled clinical trials published, and their interpretation is difficult due to the small number of patients, choice of intermediate outcomes (i.e., the reduction in antibody levels as opposed to more direct patient outcomes), and heterogeneity in patient groups. (28) Aside from cases of Goodpasture s disease, the rationale for PE in idiopathic RPGN is not as strong, due to the lack of an identifiable immune component. Studies of PE in this population have not demonstrated a significant improvement in outcome compared to the use of pulse steroid therapy. (29) Page 17

18 Antineutrophil Cytoplasmic Antibody (ANCA)-associated Vasculitis In 2011, Walsh and colleagues published a meta-analysis of studies on plasma exchange in adults with the diagnosis of either idiopathic renal vasculitis or rapidly progressive glomerulonephritis. (30) A total of 9 trials including 387 patients were identified. The clinical populations in the studies were somewhat ill-defined, but most patients appeared to have ANCA-associated vasculitis. In a pooled analysis of study findings, there was a significantly lower risk of end-stage renal disease in patients treated with adjunctive PE compared to standard care alone (RR 0.64, 95% CI: 0.47 to 0.88). The risk of death did not differ significantly in the 2 groups (RR:1.01, 95% CI: ). A relatively large RCT, included in the Walsh et al. meta-analysis, was published in 2007 by Jayne and colleagues. (31) This was a multicenter trial conducted on behalf of the European Vasculitis Study Group. The study investigated whether the addition of PE was more effective than intravenous methylprednisolone. Patients (n=137) with a new diagnosis of ANCAassociated systemic vasculitis confirmed by renal biopsy and serum creatinine greater than 500 micromol/l (5.8 mg/dl) were randomly assigned to receive 7 PEs (n=70) or 3,000 mg of intravenous methylprednisolone (n=67). Both groups received oral cyclophosphamide and oral prednisolone. The primary endpoint was dialysis independence at 3 months. Secondary endpoints included renal and patient survival at 1 year and severe adverse event rates. At 3 months, 33 (49%) of 67 were alive and independent of dialysis after intravenous methylprednisolone, as compared with 48 (69%) of 70 after PE. As compared with intravenous methylprednisolone, PE was associated with a reduction in risk for progression to end-stage renal disease of 24% at 12 months. At 1 year, the patient survival rate was 51 (76%) of 67 in the intravenous methylprednisolone group; 51 (73%) of 70 in the PE group; severe adverse event rates, 32 of 67 (48%) in the intravenous methylprednisolone group; 35 of (50%) 70 in the PE group. PE increased the rate of renal recovery in ANCA-associated systemic vasculitis that presented with renal failure when compared with intravenous methylprednisolone. Patient survival and severe adverse event rates were similar in both groups. Transplantation Solid Organ Transplant Prior to 2006, plasmapheresis in the setting of solid organ transplant was not addressed by this policy. However, plasmapheresis has been extensively used in this setting, both as pretransplant prophylaxis (i.e., desensitization) for highly sensitized patients at high risk of antibody-mediated rejection (AMR), and as a treatment of AMR after transplant. Desensitization protocols vary among transplant centers; two commonly used protocols are referred to as the Cedars-Sinai protocol and the Johns Hopkins protocol. The Cedars-Sinai protocol consists of high-dose IVIg (2 g/kg) and is offered to patients awaiting either a deceased or live donor. The Johns Hopkins protocol consists of low-dose IVIg (100 mg/kg) in combination with plasmapheresis with or without treatment with anti-cd-20 (i.e., Rituxan). Plasmapheresis is more commonly used in patients receiving a living kidney transplant from an ABO mismatched donor. (32) A variety of protocols have also been developed for the Page 18

19 treatment of AMR, often in combination with other therapies, such as IVIg or anti-cd-20. e.g. (33-35) The majority of studies of plasmapheresis in the transplant setting are retrospective case series from single institutions. Therefore, it is not possible to compare immunomodulatory regimens to determine their relative efficacy. Nevertheless, in part based on the large volume of literature published on this subject, it appears that plasmapheresis is a component of the standard of care for the management of AMR. Other conditions or applications Asthma There has been some research interest in the use of plasmapheresis in patients with severe, steroid-dependent asthma. However, preliminary results do not suggest treatment effectiveness. (36) Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections (PANDAS) and Sydenham s chorea (SC) PANDAS is defined as rapid, episodic onset of obsessive-compulsive disorder (OCD) and/or tic disorder symptoms after a group A β-hemolytic streptococcal infection (GABHS). SC is the neurologic manifestation of acute rheumatic fever. The choreatic symptoms of Sydenham s chorea are characterized by involuntary rapid and jerky movements that affect the extremities, trunk, and face. SC is generally a self-limited disorder with symptoms resolving in weeks to months. Perlmutter and colleagues conducted an RCT to evaluate the effectiveness of PE and IVIg in reducing the severity of neuropsychiatric symptoms in children diagnosed in the PANDAS subgroup. (37) Children (n=30) with clear evidence of a strep infection as the trigger of their OCD and tics were randomized to receive PE (n=10; 5 to 6 procedures over 2 weeks), IVIg (n=9; 2 gm/kg over 2 days) or placebo (n=10; mimic IVIg). All were severely ill at the time of treatment. At 1 month, both active treatment groups demonstrated symptom improvement, but those in the placebo group were unchanged. The treatment effect was still apparent after 1 year. However, 50% of the children were on the same or higher doses of their baseline medications; thus it is not entirely clear that IVIg or PE had a beneficial effect. This study needs to be replicated with a larger number of patients. The authors noted that children in the placebo group (IVIg control group) subsequently received PE in an open trial and had only minor improvements. Garvey and colleagues conducted an RCT designed to determine if IVIg or PE would be superior to prednisone in decreasing the severity of chorea. (38) Children with Syndenham s chorea (n=18) were randomized to treatment with PE (n= 8; 5 to 6 procedures over 1 to 2 weeks), IVIg (n=4; 2 gm/kg over 2 days), or prednisone (n=6; 1 mg/kg/day for 10 days followed by taper over next 10 days). The primary outcome was chorea severity at 1 month. The secondary outcome variable was chorea severity at 1 year following treatment. There was no significant difference between the baseline chorea severity scores by the treatment group. Chorea severity was assessed at baseline and at 1, 2, 3, 6, and 12 months following treatment. Page 19